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1.
Environ Monit Assess ; 194(8): 586, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35838845

RESUMO

The effluents discharged from Mansoura Company for Resins and Chemicals Industry were evaluated for drinking and irrigation purposes. Calcium-alginate beads were used for effluents treatment in this study. Young male rats were also allowed to drink effluents at different concentrations (10%, 50%, 100%) and treated 100% effluents with calcium-alginate for 11 weeks. Results indicated high concentrations of some physicochemical parameters and Cd, Co, Fe, Mn, Ni, Pb, and Zn in effluents that exceeded the permissible limits for drinking and irrigation purposes. Treatment by calcium-alginate alleviate heavy metals concentration but did not affect the physicochemical parameters. Depending on effluents concentration, the liver of young male rats showed high accumulation of Fe, Mn, Zn, Pb, Cd, Co, Cu, Cr, and Ni compared to the control group. Serum levels of liver enzymes, total bilirubin significantly increased while total protein, and albumin contents decreased in effluent groups. Liver concentrations of malondialdehyde and protein carbonyl significantly elevated along with significant decrease in superoxide dismutase, catalase, glutathione-S-transferase activities, and glutathione content. Moreover, growth and thyroid hormones were significantly reduced along with significant elevation in thyroid stimulating hormone. This was accompanied by significant decrease in the body weight, especially with 100% effluents concentration compared to control group. Also, histological investigations of both liver and thyroid gland using hematoxylin and eosin showed distortion in the structure of both organs especially with 50% and 100% effluent groups. However, treatment of effluents by calcium-alginate improved these changes. The study revealed that calcium-alginate are effective biosorbents for heavy metals and consequently decrease animal and human health hazards, but further studies are needed to alleviate physicochemical characteristics.


Assuntos
Metais Pesados , Poluentes Químicos da Água , Purificação da Água , Qualidade da Água , Alginatos/química , Animais , Cádmio/análise , Cádmio/toxicidade , Cálcio/química , Cálcio/toxicidade , Monitoramento Ambiental/métodos , Glutationa , Chumbo/análise , Chumbo/toxicidade , Masculino , Metais Pesados/análise , Metais Pesados/toxicidade , Ratos , Poluentes Químicos da Água/análise , Purificação da Água/métodos
2.
ACS Appl Mater Interfaces ; 14(1): 104-122, 2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-34958199

RESUMO

In orthopedic surgery, metals are preferred to support or treat damaged bones due to their high mechanical strength. However, the necessity for a second surgery for implant removal after healing creates problems. Therefore, biodegradable metals, especially magnesium (Mg), gained importance, although their extreme susceptibility to galvanic corrosion limits their applications. The focus of this study was to control the corrosion of Mg and enhance its biocompatibility. For this purpose, surfaces of magnesium-calcium (MgCa1) alloys were modified with calcium phosphate (CaP) or CaP doped with zinc (Zn) or gallium (Ga) via microarc oxidation. The effects of surface modifications on physical, chemical, and mechanical properties and corrosion resistance of the alloys were studied using surface profilometry, goniometry, scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), nanoindentation, and electrochemical impedance spectroscopy (EIS). The coating thickness was about 5-8 µm, with grain sizes of 43.1 nm for CaP coating and 28.2 and 58.1 nm for Zn- and Ga-doped coatings, respectively. According to EIS measurements, the capacitive response (Yc) decreased from 11.29 to 8.72 and 0.15 Ω-1 cm-2 sn upon doping with Zn and Ga, respectively. The Ecorr value, which was -1933 mV for CaP-coated samples, was found significantly electropositive at -275 mV for Ga-doped ones. All samples were cytocompatible according to indirect tests. In vitro culture with Saos-2 cells led to changes in the surface compositions of the alloys. The numbers of cells attached to the Zn-doped (2.6 × 104 cells/cm2) and Ga-doped (6.3 × 104 cells/cm2) coatings were higher than that on the surface of the undoped coating (1.0 × 103 cells/cm2). Decreased corrosivity and enhanced cell affinity of the modified MgCa alloys (CaP coated and Zn and Ga doped, with Ga-doped ones having the greatest positive effect) make them novel and promising candidates as biodegradable metallic implant materials for the treatment of bone damages and other orthopedic applications.


Assuntos
Ligas/química , Fosfatos de Cálcio/química , Materiais Revestidos Biocompatíveis/química , Implantes Absorvíveis , Ligas/toxicidade , Animais , Cálcio/química , Cálcio/toxicidade , Fosfatos de Cálcio/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Materiais Revestidos Biocompatíveis/toxicidade , Corrosão , Módulo de Elasticidade , Gálio/química , Gálio/toxicidade , Humanos , Magnésio/química , Magnésio/toxicidade , Teste de Materiais , Camundongos , Molhabilidade , Zinco/química , Zinco/toxicidade
3.
Sci Rep ; 11(1): 16526, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34400746

RESUMO

The quality and quantity of groundwater resources are affected by landuse/landcover (LULC) dynamics, particularly the increasing urbanization coupled with high household wastewater discharge and decreasing open lands. This study evaluates temporal changes of groundwater quality for 2012 and 2019, its relation to Landuse/landcover, and its impact on Peshawar's residents (study area), Pakistan. A total of 105 and 112 groundwater samples were collected from tube wells in 2012 and 2019. Samples were then analyzed for seven standard water quality parameters (i.e., pH, electric conductivity (EC), turbidity, chloride, calcium, magnesium, and nitrate). Patient data for waterborne diseases were also collected for the years 2012 and 2019 to relate the impact of groundwater quality on human health. Landsat satellite images were classified for the years 2012 and 2019 to observe landuse/landcover dynamics concerning groundwater quality. Results manifested a decrease in groundwater quality for the year 2019 compared to 2012 and were more highlighted in highly populated areas. The nitrate concentration level was found high in the vicinity of agricultural areas due to the excessive use of nitrogenous fertilizers and pesticides, and thus the methemoglobinemia patients ratio increased by 14% (48-62% for the year 2012 and 2019, respectively). Besides, Urinary Tract Infections, Peptic Ulcer, and Dental Caries diseases increased due to the high calcium and magnesium concentration. The overall results indicate that anthropogenic activities were the main driver of Spatio-temporal variability in groundwater quality of the study area. The study could help district health administration understand groundwater quality trends, make appropriate site-specific policies, and formulate future health regulations.


Assuntos
Água Subterrânea/análise , Qualidade da Água , Agricultura , Cálcio/análise , Cálcio/toxicidade , Cloretos/análise , Cárie Dentária/epidemiologia , Condutividade Elétrica , Geografia Médica , Atividades Humanas , Humanos , Concentração de Íons de Hidrogênio , Magnésio/análise , Magnésio/toxicidade , Metemoglobinemia/epidemiologia , Nefelometria e Turbidimetria , Nitratos/análise , Paquistão/epidemiologia , Úlcera Péptica/epidemiologia , Resíduos de Praguicidas/análise , Resíduos de Praguicidas/toxicidade , Saúde da População Rural , Saúde da População Urbana , Urbanização , Infecções Urinárias/epidemiologia , Águas Residuárias , Poluentes Químicos da Água/análise , Purificação da Água , Poços de Água
4.
BMC Neurosci ; 22(1): 46, 2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34301200

RESUMO

BACKGROUND: Rodent brain slices-particularly hippocampal slices-are widely used in experimental investigations of epileptiform activity. Oxygenated artificial cerebrospinal fluid (ACSF) is used to maintain slices in vitro. Physiological or standard ACSF containing 3-3.5 mM K+, 1-2 mM Mg2+, and 1-3 mM Ca2+ generally does not induce population epileptiform activity, which can be induced by ACSF with high K+ (8-10 mM), low Mg2+, or low Ca2+ alone or in combination. While low-Mg2+ ACSF without intentionally added Mg salt but with contaminating Mg2+ (≤ 50-80 µM) from other salts can induce robust epileptiform activity in slices, it is unclear whether such epileptiform activity can be achieved using ACSF with moderately decreased Mg2+. To explore this issue, we examined the effects of moderately modified (m)ACSF with 0.8 mM Mg2+, 1.3 mM Ca2+, and 5.7 mM K+ on induction of epileptiform discharges in mouse hippocampal slices. RESULTS: Hippocampal slices were prepared from young (21-28 days old), middle-aged (13-14 months old), and aged (24-26 months old) C57/BL6 mice. Conventional thin (0.4 mm) and thick (0.6 mm) slices were obtained using a vibratome and pretreated with mACSF at 35-36 °C for 1 h prior to recordings. During perfusion with mACSF at 35-36 °C, spontaneous or self-sustained epileptiform field potentials following high-frequency stimulation were frequently recorded in slices pretreated with mACSF but not in those without the pretreatment. Seizure-like ictal discharges were more common in thick slices than in thin slices. CONCLUSIONS: Prolonged exposure to mACSF by pretreatment and subsequent perfusion can induce epileptiform field potentials in mouse hippocampal slices.


Assuntos
Cálcio/metabolismo , Líquido Extracelular/metabolismo , Hipocampo/metabolismo , Magnésio/metabolismo , Potássio/metabolismo , Convulsões/metabolismo , Fatores Etários , Animais , Cálcio/toxicidade , Líquido Extracelular/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Magnésio/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Cultura de Órgãos , Potássio/toxicidade , Convulsões/induzido quimicamente , Convulsões/fisiopatologia
5.
Plant Mol Biol ; 105(1-2): 115-132, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32926249

RESUMO

KEY MESSAGE: Over-expression of CAX3 encoding a cation/proton exchanger enhances Cd tolerance by decreasing ROS (Reactive Oxygen Species) through activating anti-oxidative enzymes via elevation of Ca level in Arabidopsis CAXs (cation/proton exchangers) are involved in the sequestration of cations such as Mn, Li, and Cd, as well as Ca, from cytosol into the vacuole using proton gradients. In addition, it has been reported that CAX1, 2 and 4 are involved in Cd tolerance. Interestingly, it has been reported that CAX3 expressions were enhanced by Cd in Cd-tolerant transgenic plants expressing Hb1 (hemoglobin 1) or UBC1 (Ub-conjugating enzyme 1). Therefore, to investigate whether CAX3 plays a role in increasing Cd tolerance, CAX3 of Arabidopsis and tobacco were over-expressed in Arabidopsis thaliana. Compared to control plants, both transgenic plants displayed an increase in Cd tolerance, no change in Cd accumulation, and enhanced Ca levels. In support of these, AtCAX3-Arabidopsis showed no change in expressions of Cd transporters, but reduced expressions of Ca exporters and lower rate of Ca efflux. By contrast, atcax3 knockout Arabidopsis exhibited a reduced Cd tolerance, while the Cd level was not altered. The expression of Δ90-AtCAX3 (deletion of autoinhibitory domain) increased Cd and Ca tolerance in yeast, while AtCAX3 expression did not. Interestingly, less accumulation of ROS (H2O2 and O2-) was observed in CAX3-expressing transgenic plants and was accompanied with higher antioxidant enzyme activities (SOD, CAT, GR). Taken together, CAX3 over-expression may enhance Cd tolerance by decreasing Cd-induced ROS production by activating antioxidant enzymes and by intervening the positive feedback circuit between ROS generation and Cd-induced spikes of cytoplasmic Ca.


Assuntos
Antiporters/metabolismo , Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Cádmio/metabolismo , Cálcio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sequência de Aminoácidos , Antiporters/genética , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Transporte Biológico , Cádmio/toxicidade , Cálcio/toxicidade , Cátions/metabolismo , Tolerância a Medicamentos , Regulação da Expressão Gênica de Plantas , Técnicas de Inativação de Genes , Raízes de Plantas/metabolismo , Plantas Geneticamente Modificadas/metabolismo , Prótons , Homologia de Sequência de Aminoácidos , Nicotiana/genética , Vacúolos/metabolismo
6.
Chemosphere ; 263: 128021, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33078709

RESUMO

BACKGROUND: Metals play an important role in type 2 diabetes mellitus (T2DM). This study aimed to explore the association of T2DM risk with single metal exposure and multi-metal co-exposure. METHODS: A case-control study with 223 T2DM patients and 302 controls was conducted. Serum concentrations of 19 metals were determined by inductively coupled plasma mass spectrometry (ICP-MS). Those metals with greater effects were screened out and co-exposure effects of metals were assessed by least absolute shrinkage and selection operator (LASSO) regression. RESULTS: Serum calcium (Ca), selenium (Se) and vanadium (V) were found with greater effects. Higher levels of Ca and Se were associated with increased T2DM risk (OR = 2.23, 95%CI: 1.38-3.62, Ptrend = 0.002; OR = 3.16, 95%CI: 1.82-5.50, Ptrend < 0.001), but higher V level was associated with decreased T2DM risk (OR = 0.58, 95%CI: 0.34-0.97, Ptrend < 0.001). Serum Ca and V concentrations were nonlinearly associated with T2DM risk (Poverall < 0.001, Pnonliearity < 0.001); however, Se concentration was linearly associated with T2DM risk (Poverall < 0.001, Pnonliearity = 0.389). High co-exposure score of serum Ca, Se and V was associated with increased T2DM risk (OR = 3.50, 95%CI: 2.08-5.89, Ptrend < 0.001) as a non-linear relationship (Poverall < 0.001, Pnonliearity = 0.003). CONCLUSIONS: This study suggest that higher levels of serum Ca and Se were associated with increased T2DM risk, but higher serum V level was associated with decreased T2DM risk. Moreover, co-exposure of serum Ca, Se and V was nonlinearly associated with T2DM risk, and high co-exposure score was positively associated with T2DM risk.


Assuntos
Cálcio/toxicidade , Diabetes Mellitus Tipo 2/epidemiologia , Exposição Ambiental/estatística & dados numéricos , Poluentes Ambientais/toxicidade , Selênio/toxicidade , Vanádio/toxicidade , Adulto , Povo Asiático , Cálcio/sangue , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Poluentes Ambientais/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Selênio/sangue , Vanádio/sangue
7.
Biomolecules ; 11(1)2020 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-33374671

RESUMO

Accumulation of toxic metals in infants/children is of serious concern worldwide, from the viewpoint of their harmful effects on the normal growth and development. This metallomics study investigates the extent of toxic metal burdens in infants/children and the relationship to those in their mothers for 77 child/mother pair subjects. For mercury, its geometric mean concentration in infants/children was of similar level to that in their mothers, and a high-significant close correlation was observed between infants/children and their mothers (ß = 0.758, r = 0.539, p < 0.0001). A significant but less intimate mother/child relationship was observed for arsenic (ß = 0.301, r = 0.433), lead (ß = 0.444, r = 0.471) and aluminum (ß = 0.379, r = 0.451). Remarkably, the burden levels of lead, cadmium and aluminum in infants/children were approximately three times higher than those in their mothers (p < 0.0001), and the burden levels in some individuals were several tens of times higher than in the mothers. In contrast, some essential metal levels such as zinc, magnesium and calcium in infants/children were significantly lower than those in their mothers, and 29 individuals (37.7%) in the child subjects were estimated to be zinc-deficient. In addition, significant inverse correlations were observed between zinc and lead (r = -0.267, p = 0.019), and magnesium and arsenic (r = -0.514, p < 0.0001). These findings suggest that these toxic metal burdens and essential metal deficiencies in infants/children are of serious concern for their neurodevelopment, indicating that the early assessment and intervention are crucial. It is expected that larger epidemiological and intervention studies will provide a reasonable and essential pathway for intervention of neurodevelopment disorders.


Assuntos
Mercúrio/isolamento & purificação , Metais/toxicidade , Relações Mãe-Filho , Arsênio/toxicidade , Cádmio/toxicidade , Cálcio/isolamento & purificação , Cálcio/toxicidade , Criança , Feminino , Humanos , Lactente , Recém-Nascido , Magnésio/isolamento & purificação , Magnésio/toxicidade , Masculino , Mercúrio/toxicidade , Metais/sangue , Metais/isolamento & purificação , Mães , Gravidez , Zinco/isolamento & purificação , Zinco/toxicidade
8.
Cell Death Dis ; 11(12): 1039, 2020 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-33288740

RESUMO

Therapy resistance is a major roadblock in oncology. Exacerbation of molecular dysfunctions typical of cancer cells have proven effective in twisting oncogenic mechanisms to lethal conditions, thus offering new therapeutic avenues for cancer treatment. Here, we demonstrate that selective agonists of Transient Receptor Potential cation channel subfamily M member 8 (TRPM8), a cation channel characteristic of the prostate epithelium frequently overexpressed in advanced stage III/IV prostate cancers (PCa), sensitize therapy refractory models of PCa to radio, chemo or hormonal treatment. Overall, our study demonstrates that pharmacological-induced Ca2+ cytotoxicity is an actionable strategy to sensitize cancer cells to standard therapies.


Assuntos
Cálcio/toxicidade , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Anilidas/farmacologia , Apoptose/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Masculino , Mentol/análogos & derivados , Mentol/farmacologia , Modelos Biológicos , Estadiamento de Neoplasias , Canais de Cátion TRPM/metabolismo , Raios X
9.
Chemosphere ; 258: 127408, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32782161

RESUMO

This study investigates the impacts of exposure to an environment Ca2+ challenge and the mechanism of action of dibutyl phthalate (DBP) on Ca2+ influx in the gills of Danio rerio. In vitro profile of 45Ca2+ influx in gills was verified through the basal time-course. Fish were exposed to low, normal and high Ca2+ concentrations (0.02, 0.7 and 2 mM) for 12 h. So, gills were morphologically analysed and ex vivo45Ca2+ influx at 30 and 60 min was determined. For the in vitro studies, gills were treated for 60 min with DBP (1 pM, 1 nM and 1 µM) with/without blockers/activators of ionic channels, Ca2+ chelator, inhibitors of ATPases, ionic exchangers and protein kinase C to study the mechanism of DBP-induced 45Ca2+ influx. Exposure to high environmental Ca2+ augmented 45Ca2+ influx when compared to fish exposed to normal and low Ca2+ concentrations. Additionally, histopathological changes were observed in the gills of fish maintained for 12 h in low and high Ca2+. In vitro exposure of gills to DBP (1 pM) disturbed Ca2+ homeostasis. DBP stimulated 45Ca2+ influx in gills through the transitory receptor potential vanilloid 1 (TRPV1), and reverse-mode Na+/Ca2+ exchanger (NCX) activation, protein kinase C and K+ channels and sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). These data suggest that in vivo short-term exposure of gills to low and high Ca2+ leads to 45Ca2+ influx and histopathological changes. Additionally, the DBP-induced rapid 45Ca2+ influx is mediated by TRPV1, NCX activation with the involvement of PKC, K+-channels and SERCA, thereby altering Ca2+ homeostasis.


Assuntos
Radioisótopos de Cálcio/metabolismo , Cálcio/metabolismo , Dibutilftalato/toxicidade , Brânquias/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/metabolismo , Animais , Cálcio/toxicidade , Dibutilftalato/metabolismo , Retículo Endoplasmático/metabolismo , Brânquias/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Canais de Cátion TRPV/metabolismo , Poluentes Químicos da Água/metabolismo
10.
J Appl Toxicol ; 40(8): 1076-1086, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32163192

RESUMO

Metal exposure has recently been related to the risk of hypertension. However, the association remains unclear and relevant epidemiologic studies are limited. The present study aimed to assess the associations between exposure to metals and the odds of hypertension, as well as blood pressure (BP) levels. A total of 816 participants were enrolled in southwestern China. Hypertension was defined as a systolic BP (SBP) of ≥140 mmHg or diastolic BP (DBP) of ≥90 mmHg, a self-reported physician diagnosis, or current use of antihypertensive medication. Blood samples were used to detect the levels of exposure to metals, ie, magnesium (Mg), calcium (Ca), iron (Fe), zinc (Zn), arsenic (As), cadmium (Cd), copper (Cu) and lead (Pb). Logistic and linear regression models were used to assess the potential associations. The results show that positive trends for elevated odds of hypertension with increasing quartiles of Fe in a polluted area; and of Mg, Ca and Cu in an unpolluted area. Compared with those in the lowest quartiles, participants in the highest quartiles of Fe, Mg and Ca had 2.7-, 9.0- and 5.1-fold increased odds of hypertension, respectively. High blood Fe and Pb levels in the Cd-polluted area, and Mg and Fe in the unpolluted area were found to be related to increasing SBP and DBP levels. Our findings suggest that exposure to Fe and/or Pb in the polluted area; and Mg, Ca and Fe in the unpolluted area might increase the risk of hypertension or elevate BP levels.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Exposição Ambiental/efeitos adversos , Exposição Ambiental/estatística & dados numéricos , Poluentes Ambientais/sangue , Hipertensão/induzido quimicamente , Metais Pesados/sangue , Metais Pesados/toxicidade , Adulto , Idoso , Arsênio/sangue , Arsênio/toxicidade , Cádmio/sangue , Cádmio/toxicidade , Cálcio/sangue , Cálcio/toxicidade , China , Cobre/sangue , Cobre/toxicidade , Feminino , Humanos , Ferro/sangue , Ferro/toxicidade , Magnésio/sangue , Magnésio/toxicidade , Masculino , Pessoa de Meia-Idade , Razão de Chances , Zinco/sangue , Zinco/toxicidade
11.
Diabetes ; 69(5): 1032-1041, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32079579

RESUMO

Type 2 diabetes (T2D) is caused by loss of pancreatic ß-cell mass and failure of the remaining ß-cells to deliver sufficient insulin to meet demand. ß-Cell glucolipotoxicity (GLT), which refers to combined, deleterious effects of elevated glucose and fatty acid levels on ß-cell function and survival, contributes to T2D-associated ß-cell failure. Drugs and mechanisms that protect ß-cells from GLT stress could potentially improve metabolic control in patients with T2D. In a phenotypic screen seeking low-molecular-weight compounds that protected ß-cells from GLT, we identified compound A that selectively blocked GLT-induced apoptosis in rat insulinoma cells. Compound A and its optimized analogs also improved viability and function in primary rat and human islets under GLT. We discovered that compound A analogs decreased GLT-induced cytosolic calcium influx in islet cells, and all measured ß-cell-protective effects correlated with this activity. Further studies revealed that the active compound from this series largely reversed GLT-induced global transcriptional changes. Our results suggest that taming cytosolic calcium overload in pancreatic islets can improve ß-cell survival and function under GLT stress and thus could be an effective strategy for T2D treatment.


Assuntos
Canais de Cálcio Tipo L/metabolismo , Cálcio/toxicidade , Glicolipídeos/antagonistas & inibidores , Glicolipídeos/toxicidade , Células Secretoras de Insulina/efeitos dos fármacos , Animais , Apoptose , Linhagem Celular , Sobrevivência Celular , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Transcriptoma
12.
J Neurosci ; 40(9): 1975-1986, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-32005765

RESUMO

Mitochondrial dysfunction is critically involved in Parkinson's disease, characterized by loss of dopaminergic neurons (DaNs) in the substantia nigra (SNc), whereas DaNs in the neighboring ventral tegmental area (VTA) are much less affected. In contrast to VTA, SNc DaNs engage calcium channels to generate action potentials, which lead to oxidant stress by yet unknown pathways. To determine the molecular mechanisms linking calcium load with selective cell death in the presence of mitochondrial deficiency, we analyzed the mitochondrial redox state and the mitochondrial membrane potential in mice of both sexes with genetically induced, severe mitochondrial dysfunction in DaNs (MitoPark mice), at the same time expressing a redox-sensitive GFP targeted to the mitochondrial matrix. Despite mitochondrial insufficiency in all DaNs, exclusively SNc neurons showed an oxidized redox-system, i.e., a low reduced/oxidized glutathione (GSH-GSSG) ratio. This was mimicked by cyanide, but not by rotenone or antimycin A, making the involvement of reactive oxygen species rather unlikely. Surprisingly, a high mitochondrial inner membrane potential was maintained in MitoPark SNc DaNs. Antagonizing calcium influx into the cell and into mitochondria, respectively, rescued the disturbed redox ratio and induced further hyperpolarization of the inner mitochondrial membrane. Our data therefore show that the constant calcium load in SNc DaNs is counterbalanced by a high mitochondrial inner membrane potential, even under conditions of severe mitochondrial dysfunction, but triggers a detrimental imbalance in the mitochondrial redox system, which will lead to neuron death. Our findings thus reveal a new mechanism, redox imbalance, which underlies the differential vulnerability of DaNs to mitochondrial defects.SIGNIFICANCE STATEMENT Parkinson's disease is characterized by the preferential degeneration of dopaminergic neurons (DaNs) of the substantia nigra pars compacta (SNc), resulting in the characteristic hypokinesia in patients. Ubiquitous pathological triggers cannot be responsible for the selective neuron loss. Here we show that mitochondrial impairment together with elevated calcium burden destabilize the mitochondrial antioxidant defense only in SNc DaNs, and thus promote the increased vulnerability of this neuron population.


Assuntos
Antioxidantes/metabolismo , Cálcio/toxicidade , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Substância Negra/metabolismo , Substância Negra/patologia , Animais , Calbindina 1/metabolismo , Morte Celular , Cianetos/toxicidade , Feminino , Masculino , Potencial da Membrana Mitocondrial , Camundongos , Membranas Mitocondriais/metabolismo , Oxirredução , Estresse Oxidativo , Área Tegmentar Ventral/metabolismo , Área Tegmentar Ventral/patologia
13.
Int J Mol Sci ; 20(23)2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31775364

RESUMO

In chronic kidney disease (CKD), the first cause of mortality is cardiovascular disease induced mainly by vascular calcification (VC). Recently, iron-based phosphate binders have been proposed in advanced CKD to treat hyperphosphatemia. We studied the effect of iron citrate (iron) on the progression of calcification in high-phosphate (Pi) calcified VSMC. Iron arrested further calcification when added on days 7-15 in the presence of high Pi (1.30 ± 0.03 vs 0.61 ± 0.02; OD/mg protein; day 15; Pi vs Pi + Fe, p < 0.01). We next investigated apoptosis and autophagy. Adding iron to high-Pi-treated VSMC, on days 7-11, decreased apoptotic cell number (17.3 ± 2.6 vs 11.6 ± 1.6; Annexin V; % positive cells; day 11; Pi vs Pi + Fe; p < 0.05). The result was confirmed thorough analysis of apoptotic nuclei both in VSMCs and aortic rings treated on days 7-15 (3.8 ± 0.2 vs 2.3 ± 0.3 and 4.0 ± 0.3 vs 2.2 ± 0.2; apoptotic nuclei; arbitrary score; day 15; Pi vs Pi + Fe; VSMCs and aortic rings; p < 0.05). Studying the prosurvival axis GAS6/AXL, we found that iron treatment on days 9-14 counteracted protein high-Pi-stimulated down-regulation and induced its de novo synthesis. Moreover, iron added on days 9-15 potentiated autophagy, as detected by an increased number of autophagosomes with damaged mitochondria and an increase in autophagic flux. Highlighting the effect of iron on apoptosis, we demonstrated its action in blocking the H2O2-induced increase in calcification added both before high Pi treatment and when the calcification was already exacerbated. In conclusion, we demonstrate that iron arrests further high Pi-induced calcium deposition through an anti-apoptotic action and the induction of autophagy on established calcified VSMC.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia , Cálcio/toxicidade , Compostos Férricos/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Fosfatos/toxicidade , Calcificação Vascular/tratamento farmacológico , Animais , Células Cultivadas , Músculo Liso Vascular/patologia , Ratos , Calcificação Vascular/induzido quimicamente , Calcificação Vascular/patologia
14.
Brain ; 142(9): 2737-2755, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31302671

RESUMO

Poor vitamin D status is associated with a higher relapse rate and earlier disability in multiple sclerosis. Based on these associations, patients with multiple sclerosis are frequently supplemented with the vitamin D precursor cholecalciferol, although it is unclear whether this regimen is of therapeutic benefit. To model consequences of this common practice, mice were fed for more than 3 months with a low, medium or high dose of cholecalciferol, representative of vitamin D deficiency, modest and disproportionally high supplementation, respectively, in patients with multiple sclerosis. Compared to vitamin D-deprived mice, its moderate supplementation reduced the severity of subsequent experimental autoimmune encephalomyelitis, which was associated with an expansion of regulatory T cells. Direct exposure of murine or human T cells to vitamin D metabolites inhibited their activation. In contrast, mice with 25-(OH) vitamin D levels above 200 nmol/l developed fulminant experimental autoimmune encephalomyelitis with massive CNS infiltration of activated myeloid cells, Th1 and Th17 cells. When dissecting this unexpected outcome, we observed that high, but not medium dose vitamin D had caused mild hypercalcaemia, which rendered T cells more prone to pro-inflammatory activation. Exposing murine or human T cells to equivalent calcium concentrations in vitro enhanced its influx, triggering activation, upregulation of pro-inflammatory gene products and enhanced transmigration across a blood-brain barrier model. These findings suggest that vitamin D at moderate levels may exert a direct regulatory effect, while continuous high dose vitamin D treatment could trigger multiple sclerosis disease activity by raising mean levels of T-cell excitatory calcium.


Assuntos
Autoimunidade/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Subpopulações de Linfócitos T/efeitos dos fármacos , Vitamina D/toxicidade , Animais , Barreira Hematoencefálica , Calcifediol/sangue , Cálcio/sangue , Cálcio/uso terapêutico , Cálcio/toxicidade , Cloretos/sangue , Colecalciferol/efeitos adversos , Colecalciferol/uso terapêutico , Relação Dose-Resposta a Droga , Encefalomielite Autoimune Experimental/imunologia , Feminino , Humanos , Hipercalcemia/induzido quimicamente , Hipercalcemia/imunologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Esclerose Múltipla/complicações , Esclerose Múltipla/imunologia , Fosfatos/sangue , Sódio/sangue , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Vitamina D/sangue , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/tratamento farmacológico , Deficiência de Vitamina D/imunologia
15.
Artigo em Inglês | MEDLINE | ID: mdl-30419361

RESUMO

Cadmium is a persistent contaminant of surface waters. The effects of cadmium on early life stages of fish are not well understood, although they are often disproportionately affected by contaminants. The objectives of this study were to examine effects of chronic exposure to environmentally relevant concentrations on growth, development, cellular stress, and glucose metabolism of channel catfish, Ictalurus punctatus. Eggs were wet-fertilized in treatment water at concentrations of 0.4 (control), 2.2 (low), or 8.5 (high) µg L-1 and monitored through swim-up, black fry stage. Eggs and fry accumulated cadmium dose-dependently. Fertilization rates were unaffected, yet hatch rate was significantly reduced in the high treatment. Survival to black fry and overall size and condition factor were not affected; however, differences in yolk sac size, and presumably energetics of yolk fry, was detected. Physiological pathways were also affected, demonstrated by altered gene expression, most notably in genes related to carbohydrate metabolism. Elevated expression of HK and G6PD, rather than G6P and GADPH, suggests glucose may be shunted towards the pentose-phosphate pathway. Overall, observations indicate cadmium negatively affects development in early life stages of channel catfish, which could lead to shifts in population structure and life history patterns in exposed populations of wild fish.


Assuntos
Cádmio/toxicidade , Ictaluridae/crescimento & desenvolvimento , Poluentes Químicos da Água/toxicidade , Animais , Cálcio/toxicidade , Metabolismo dos Carboidratos/efeitos dos fármacos , Relação Dose-Resposta a Droga , Exposição Ambiental/efeitos adversos , Expressão Gênica/efeitos dos fármacos , Zinco/toxicidade
16.
Regul Toxicol Pharmacol ; 100: 68-71, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30359700

RESUMO

ß-Hydroxy-ß-methylbutyrate (HMB) is a leucine metabolite available in calcium salt (CaHMB) and free acid forms as a sports nutrition ergogenic aid. HMB has also been used to support muscle health in the elderly and other populations needing to maintain muscle mass. Several human studies have reported safety data for CaHMB, and rodent sub-chronic toxicity studies have been conducted; however, there are no published genotoxicity studies for HMB. Therefore, three studies (a bacterial reverse mutation test, an in vitro mammalian chromosomal aberration test, and an in vivo mammalian cell micronucleus test) were performed. In the Ames test, no changes in revertant colonies or background were noted with CaHMB concentrations up to 5000 µg per plate, either with or without metabolic activation in five bacterial strains. In the chromosomal aberration test, the number of aberrations associated with up to 2.5 mM CaHMB (long-term) or 10.0 mM (short-term) were similar to those observed for negative controls (<5%), and no polyploidy was observed. Lastly, in the mammalian micronucleus test, no changes in immature erythrocyte or micronuclei frequencies were observed in animals treated with up to 2000 mg·kg-1 body weight CaHMB. In conclusion, CaHMB was determined to have no genotoxic effects.


Assuntos
Cálcio/toxicidade , Valeratos/toxicidade , Animais , Células da Medula Óssea/efeitos dos fármacos , Linhagem Celular , Aberrações Cromossômicas , Cricetulus , Eritrócitos/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Masculino , Camundongos Endogâmicos ICR , Testes de Mutagenicidade , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética
17.
Acupunct Med ; 36(6): 401-407, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30257960

RESUMO

BACKGROUND: The hippocampus is vulnerable to severe damage after cerebral ischaemia-reperfusion (I/R) injury. This study aimed to explore the effect of electroacupuncture (EA) on cognitive impairment and its relationship with Ca2+neurotoxicity in a rat model of I/R injury induced by middle cerebral artery occlusion (MCAO). METHODS: 60 adult male Sprague-Dawley rats were randomly divided into three groups: control (sham surgery) group, untreated MCAO group and EA-treated MCAO+EA group. Rats in the MCAO and MCAO+EA groups underwent modelling of poststroke cognitive impairment by MCAO surgery. EA was performed for 30 min daily at GV20 and GV24 (1-20 Hz) for 1 week. The Morris water maze experiment was used to assess cognitive function. 2,3,5-triphenyl tetrazolium chloride staining was used to measure infarct volume. The intracellular Ca2+content in the Cornu Ammonis (CA)1 area of the hippocampus was assessed by laser confocal scanning microscopy. ELISA was performed to evaluate the concentration of glutamate (Glu) in the hippocampus, and the protein expression of two Glu receptors (N-methyl-D-aspartic acid receptor (NMDAR) 2A and NMDAR2B) were analysed by Western blotting. RESULTS: Compared with the untreated MCAO group, EA effectively ameliorated cognitive impairment (P=0.01) and shrunk the infarct volume (P=0.032). The content of intracellular Ca2+, Glu and NMDAR2B in the hippocampus was significantly raised by MCAO (P=0.031-0.043), while EA abrogated these effects. NMDAR2A was decreased by MCAO (P=0.015) but increased by EA (P=0.033). CONCLUSIONS: EA had a beneficial effect on cognitive repair after cerebral I/R, and its mechanism of action likely involves a reduction of Ca2+influx via inhibition of Glu neurotoxicity and downregulation of NMDAR2B expression.


Assuntos
Cálcio/toxicidade , Disfunção Cognitiva/terapia , Eletroacupuntura , Traumatismo por Reperfusão/terapia , Animais , Disfunção Cognitiva/etiologia , Modelos Animais de Doenças , Hipocampo/metabolismo , Infarto da Artéria Cerebral Média , Masculino , Aprendizagem em Labirinto , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/fisiopatologia
18.
Calcif Tissue Int ; 103(4): 455-464, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29882057

RESUMO

Fibroblast growth factor 23 (FGF23) is associated with mortality in patients with CKD. However, the mechanisms underlying stimulation of FGF23 remain to be investigated. We examined whether hypercalcemia induced by continuous intravenous (CIV) calcium (Ca) infusion regulates FGF23 levels in normal rats (Normal) and 5/6 nephrectomized uremic rats (Nx). Microinfusion pumps were implanted in the Normal and Nx rats for CIV Ca infusion, and blood, urine, kidney, and tibia were collected. The results showed an increase in serum Ca-stimulated FGF23 independently of serum phosphate (P) and creatinine levels in Normal and Nx rats. FGF23 mRNA from the tibia was also increased by the Ca infusion. Despite high FGF23 levels after Ca infusion, urinary P excretion was decreased. Renal α-Klotho expression was significantly reduced by Ca infusion. These results suggest that intravenous Ca loading might stimulate FGF23 production from bone in normal and uremic rats. Reduction of renal P excretion suggests that the bioactivity of FGF23 is inhibited, and the decrease in renal α-Klotho expression might have a role in this pathological process. In conclusion, CIV Ca loading increased FGF23 in normal and uremic rats, and renal α-Klotho is necessary to maintain the bioactivity of FGF23 as a phosphaturic factor.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Hipercalcemia/metabolismo , Hipercalcemia/fisiopatologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Animais , Cálcio/toxicidade , Glucuronidase/metabolismo , Proteínas Klotho , Masculino , Ratos , Ratos Sprague-Dawley , Uremia/metabolismo , Uremia/fisiopatologia
19.
Environ Sci Pollut Res Int ; 25(18): 18027-18037, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29691741

RESUMO

Formation water (FoW) is a by-product from oil and gas production and usually has high concentrations of soluble salts and metals. Calcium (Ca) and magnesium (Mg) have been shown to reduce the toxicity of metals to aquatic animals, and previous study showed that high waterborne Ca exerts mild effect against disturbances on Na+ regulation in Amazonian armored catfish tamoatá (Hoplosternum littorale) acutely exposed to high Fe, Mn, and Ba levels. Here, we hypothesized that high Mg levels might also reduce the toxic effects of these metals on Na+ regulation of tamoatá. The exposure to 5% FoW promoted an increase in Na+ uptake and a rapid accumulation of Na+ in all tissues analyzed (kidney

Assuntos
Bário/química , Cálcio/metabolismo , Peixes-Gato/metabolismo , Brânquias/metabolismo , Íons/química , Magnésio/química , Sódio/metabolismo , Poluentes Químicos da Água/análise , Animais , Bário/toxicidade , Cálcio/toxicidade , Magnésio/toxicidade , Sódio/química , Sódio/toxicidade , Poluentes Químicos da Água/química
20.
Cereb Cortex ; 28(4): 1168-1182, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28334242

RESUMO

The dorsal Lateral Geniculate Nucleus (dLGN) is the primary image-forming target of the retina and shares a reciprocal connection with primary visual cortex (V1). Previous studies showed that corticothalamic input is essential for the development of thalamocortical projections, but less is known about the potential role of this reciprocal connection in the development of retinal projections. Here, we show a deficit of retinal innervation in the dLGN around E18.5 in Tra2ß conditional knockout (cKO) "cortexless" mice, an age when apoptosis occurs along the thalamocortical tract and in some dLGN neurons. In vivo electrophysiology experiments in the dLGN further confirmed the loss of functional retinal input. Experiments with N-methyl-d-aspartic acid-induced V1 lesion as well as Fezf2 cKO mice confirmed that the disruption of connections between the dLGN and V1 lead to abnormal retinal projections to the dLGN. Interestingly, retinal projections to the ventral Lateral Geniculate Nucleus (vLGN) and Superior Colliculus (SC) were normal in all 3 mice models. Finally, we show that the cortexless mice had worse performance than control mice in a go-no go task with visual cues. Our results provide evidence that the wiring of visual circuit from the retina to the dLGN and V1 thereafter is coordinated at a surprisingly early stage of circuit development.


Assuntos
Axônios/fisiologia , Corpos Geniculados/fisiologia , Retina/citologia , Colículos Superiores/fisiologia , Córtex Visual/fisiologia , Vias Visuais/fisiologia , Potenciais de Ação/fisiologia , Animais , Animais Recém-Nascidos , Cálcio/toxicidade , Toxina da Cólera/metabolismo , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Embrião de Mamíferos , Agonistas de Aminoácidos Excitatórios/toxicidade , Comportamento Alimentar/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Fatores de Processamento de Serina-Arginina/deficiência , Fatores de Processamento de Serina-Arginina/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Córtex Visual/lesões
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